DESCRIPTION: (Applicant's Abstract) Neocortical pyramidal neurons are a model system for study of the mechanisms and significance of transduction of synaptic inputs into spike trains. Several aspects of this transduction process are Ca2+-dependent, including regulation of the interspike interval (ISI), spike frequency adaptation (SFA), spike timing and afterhyperpolarizations (AHPs). Pyramidal cells express at least five different high voltage-activated Ca2+ channels. We hypothesize that Ca2+ entry has different consequences for these cells, depending upon which calcium channel subtypes are involved. An example of such partitioning of function is generation of AHPs: N-, P-, and Q-type channels couple to the sAHP and P-type to the mAHP. Two critical negative feedback systems controlling Ca2+ entry are Ca2+-dependent inactivation of Ca2+ channels and activation of Ca2+-dependent K+ channels. Both processes are potential regulators of pyramidal cell firing behavior. We will use whole cell electrical recordings and fura-2 Ca2+ imaging techniques on mature pyramidal cells in both acutely dissociated and brain slice preparations to test hypotheses about the roles of Ca2+-dependent inactivation and the relationships between action potentials, [Ca2+]i, and AHP currents (due to Ca2+-dependent K+ channels). Aim 1 addresses the importance of Ca2+-dependent inactivation of Ca2+ channel subtypes and which channel subtypes are involved. Aim 2 characterizes the relationships between firing frequency, IAHP, and [Ca2+]i in mature pyramidal cells. These data are important for understanding how pyramidal cells integrate synaptic inputs, and how this process is influenced by transmitters and ontogeny. (In neocortical pyramidal neurons, both Ca2+ and Ca2+-dep K+ channels are developmentally regulated and are targets for several neuromodulators). Neuronal activity and its modulation regulate cortical function and the use-dependent plasticity of cortical connections. These studies will contribute to understanding essential cortical functions such as attention, learning, and memory as well as basic mechanisms of diseases such as epilepsy, anxiety and depression.